Patients with chronic hepatitis C who do not respond to antiviral treatment are at risk of progression to cirrhosis, liver failure, hepatocellular carcinoma (HCC) and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain. Hepatitis C Long-Term Treatment against Cirrhosis (HALT-C) was a randomized controlled trial of peginterferon alfa-2a (90 &#61549;g per week) for 3.5 years versus no treatment in patients with chronic hepatitis C and advanced fibrosis who were nonresponders to prior therapy with peginterferon and ribavirin. Participants were stratified by stage of fibrosis [unreadable] 622 with fibrosis and 428 with cirrhosis. Patients were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. Outcomes included death, HCC, hepatic decompensation and, for those with precirrhotic fibrosis at baseline, an increase in fibrosis score of &#8805;2 points. 1,050 patients were randomized (517 treatment, 533 control). Outcomes occurred in by 34.1% of the treatment group and 33.8% of the untreated group (hazard ratio =1.01;95% CI = 0.84-1.26;p=0.91). Serum aminotransferase levels, HCV RNA levels, and histologic necroinflammatory scores all decreased significantly (p<0.001) with treatment, but no significant difference emerged in rates of any primary outcome between groups. The rate of serious adverse events was similar in both groups (p=0.065). Among treated patients, 17% stopped peginterferon by year 1.5 and 30% by year 3.5. Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis or cirrhosis. Prior to the randomized phase, it had to be demonstrated that patients would not have sustained virological response on standard therapy of pegylated interferon and ribavirin. Because many patients respond to this lead-in therapy, approximately 1146 entered the lead-in phase resulting in about 14% with SVR. Once the combination of peg-interferon and ribavirin was approved for treatment, the protocol was amended to include patients who did not clear virus on this therapy outside of the lead-in, but otherwise met HALT-C inclusion criteria ([unreadable]express[unreadable] patients). Numerous ancillary studies were conducted focused on hepatitis C and liver disease. These included immunological, virological, and genetic studies;studies of predictors of disease progression including fatty liver, obesity, diabetes, quantitative liver function tests, serum fibrosis markers, esophageal varices, dietary constituents including coffee and caffeine, health related quality of life and depressive symptoms;validation of fibrosis staging;and biomarkers for HCC.